The candidate is an accomplished physician who completed a three year postdoctoral fellowship including graduate coursework in the sponsor's (Shaun Coughlin) laboratory prior to his clinical training in Cardiology. During this time he completed a project that addressed the molecular basis of Protease-activated receptor 2 (PAR2) agonist specificity. Using chimeric receptors expressed in Xenopus oocytes he determined PAR2's second extracellular loop dictates its agonist specificity and identified a previously undescribed interaction between the receptor's amino-terminus and third extracellular loop is required for receptor function. The Mentored Clinical Scientist Development Award will allow the candidate to strengthen his intellectual skills and acquire new technical skills to become an independent investigator in cardiovascular biology. This will prepare him to pursue his long- term research goal of defining receptor-activated signaling events that mediate atherogenesis, thrombosis, and vascular development. The research plan is designed to characterize protein interactions with Rho guanine nucleotide exchange factors (Rho GEFs) that mediate G-alpha13-coupled signaling. Specifically, the candidate will 1) identify proteins that interact with the Rho GEF Lsc to mediate G-alpha13-coupled Rho signaling events, 2) determine the role of a newly discovered interaction between Lsc and its own C- terminus in regulating its function, 3) define the role of a newly discovered Rho GEF interacting protein candidate , GIP12, in regulating G-alpha13-coupled Rho signaling. These studies will allow the candidate to develop expertise in methodologies used to interrogate receptor-mediated signal transduction including: recombinant protein purification and confocal microcopy of microinjected somatic cells expressing epitope-tagged proteins. The environment at UCSF's Cardiovascular Research Institute will expose the candidate to the newest endeavors in receptor biology and signal transduction. The sponsor's laboratory employs ten postgraduate fellows with ongoing projects focused on the C- protein-coupled thrombin receptors' activation and signaling. The candidate has assembled an Advisory Committee (Henry Bourne, Ira Herskowitz, Frank McCormick, and Arthur Weiss) at UCSF with expertise in all areas related to this proposal. Coursework in molecular and cellular biology and participation in research seminars and journal clubs at UCSF will provide the candidate with a review of receptor-mediated process as they relate to human disease.